Background/Objectives: Despite advances in hepatocellular carcinoma (HCC) management, prognosis remains poor. Advanced-stage diagnosis often excludes curative treatments, and current biomarkers (e.g., alpha-fetoprotein [AFP]) have limited utility in early detection. Liquid biopsy has emerged as a promising cancer detection tool, with circulating cell-free DNA (ccfDNA) showing significant diagnostic potential. This proof-of-concept study aimed to investigate the potential role of tumor fraction (TF) within ccfDNA as a biomarker in HCC patients. Methods: A total of sixty patients were recruited, including thirteen with chronic liver disease (CLD), twenty-four with cirrhosis, and twenty-three with HCC. Plasma samples were collected, and ccfDNA was extracted for shallow whole genome sequencing (sWGS) analysis. The TF was calculated by focusing on somatic copy number alterations (SCNAs) within the ccfDNA. Results: Among patients with CLD and cirrhosis (n = 37), ctDNA was undetectable in all but one cirrhotic patient who exhibited a significant tumor fraction (TF) of 17% and subsequently developed HCC. Conversely, five out of twenty-three HCC patients (21.7%) displayed detectable ctDNA with TF levels ranging from 3.0% to 32.6%. Patients with detectable ctDNA were characterized by more aggressive oncological features, including a higher number of nodules (p= 0.005), advanced-stage disease (60% BCLC C,p= 0.010), and poorer response to therapy (80% PD,p= 0.001). Moreover, the overall survival (OS) was significantly reduced in patients with detectable ctDNA (median OS: 17 months; CI 95% 4.5–26.5) compared to those without (median OS: 24.0 months; CI 95% 7.0–66.0; log-rankp= 0.002). Conclusions: Our results suggest that the analysis of TF by sWGS is a promising non-invasive tool for the identification of HCC with aggressive clinical behavior, whereas it is not sensitive enough for early HCC detection. This molecular assay can improve prognostic stratification in HCC patients.
背景/目的：尽管肝细胞癌（HCC）的治疗已取得进展，但其预后仍然较差。晚期诊断常使患者失去根治性治疗机会，而现有生物标志物（如甲胎蛋白[AFP]）在早期检测中的效用有限。液体活检已成为一种有前景的癌症检测工具，其中循环游离DNA（ccfDNA）显示出显著的诊断潜力。本概念验证研究旨在探讨ccfDNA中肿瘤分数（TF）作为HCC患者生物标志物的潜在作用。方法：共招募60例患者，包括13例慢性肝病（CLD）患者、24例肝硬化患者和23例HCC患者。收集血浆样本并提取ccfDNA进行低深度全基因组测序（sWGS）分析。通过聚焦ccfDNA中的体细胞拷贝数变异（SCNAs）计算TF。结果：在CLD和肝硬化患者（n=37）中，除1例肝硬化患者外均未检测到循环肿瘤DNA（ctDNA）；该例外患者表现出高达17%的肿瘤分数（TF），并在后续进展为HCC。相反，23例HCC患者中有5例（21.7%）检测到ctDNA，TF水平介于3.0%至32.6%之间。可检测到ctDNA的患者具有更具侵袭性的肿瘤特征，包括更多结节数量（p=0.005）、更晚分期（60%为BCLC C期，p=0.010）以及对治疗更差的反应（80%为疾病进展，p=0.001）。此外，与未检测到ctDNA的患者相比（中位总生存期：24.0个月；95% CI 7.0–66.0），可检测到ctDNA的患者总生存期（OS）显著缩短（中位OS：17个月；95% CI 4.5–26.5；对数秩检验p=0.002）。结论：我们的研究结果表明，通过sWGS分析TF是一种有前景的非侵入性工具，可用于识别具有侵袭性临床行为的HCC，但其对早期HCC检测的敏感性不足。该分子检测方法可改善HCC患者的预后分层。
肿瘤(癌症)患者之家